Metabolic vulnerabilities in pleural mesothelioma

Mesothelioma is a rare tumour of mesothelial origin that is often diagnosed at advanced stages. Despite recent approval of immunotherapy, the prognosis of mesothelioma remains dismal. Growing evidence links tumour metabolism to the molecular mechanisms driving mesothelioma's aggressiveness, therapeutic resistance and poor outcomes. Mesothelioma-specific metabolic alterations may be derived from asbestos-induced chronic inflammation, the mesothelial origin, the pleural microenvironment and tumour-stroma interactions, as well as recurrent genomic alterations that distinguish mesothelioma from malignancies of the lung parenchyma. Elucidating these metabolic alterations is therefore crucial for identifying exploitable vulnerabilities and improving therapeutic strategies. Key metabolic pathways, including glycolysis, the pentose phosphate pathway, nucleotide biosynthesis and amino acid and lipid metabolism, are tightly interconnected within a dynamic network that regulates cell survival and proliferation. Metabolism also shapes tumour microenvironment by regulating redox homoeostasis, signalling and nutrient exchange. Considering these pathways in isolation provides an incomplete picture, and instead, studying them as a whole, and building a coherent metabolic map is essential for revealing context-specific dependencies. In this review, we summarise current knowledge of mesothelioma metabolism, highlighting how recurrent genetic alterations including CDKN2A, MTAP, BAP1, NF2 and TP53 influence metabolic phenotypes. We discuss experimental and therapeutic efforts that target individual metabolic branches and evaluate how these insights can inform a unified strategy to exploit metabolic weaknesses and guide the rational development of combination therapies.